Researchers have observed that endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. The role of endothelium in maintaining cardiovascular health is fairly well documented. Endothelial dysfunction and coronary artery disease (CAD) are also linked to hypertension, hypercholesterolemia diabetes mellitus and cigarette smoking. Dietary and lifestyle modification, in addition to anti-oxidant vitamin supplementation, have been demonstrated to have a beneficial affect on endothelial function. Clinical Implications of Endothelial Dysfunction, C. Pepine, Clinical Cardiology, Vol. 21, November, 1998, pp. 795-799. Other researchers have observed that the vascular endothelium, the cells lining the interior portion of arteries, plays a fundamental role in several processes related to hemostasis thrombosis. These researchers have proposed that endothelial function may provide guidance to developing new strategies for coronary disease prevention and treatment. Nontraditional Coronary Risk Factors and Vascular Biology: The Frontiers of Preventive Cardiology, by P. Ridker et al., J. of Investigative Medicine, Vol. 46, No. 8, October, 1998, pp. 348-350. At present, the full range of different diseases associated with endothelial dysfunction remains to be determined, the nature of the abnormalities defined and measured, and the effects of potential treatments evaluated.
To some degree, the health and the condition of the endothelium is also related to the ability of that cellular layer to generate and transmit nitric oxide (NO) as a biomarker throughout the tissues of the arterial wall. Most recently, Nobel Prize winners Robert F. Furchgott, Ferid Murad and Louis J. Ignarro have linked the production and transmission of NO through the endothelium as being the primary indicator associated with vascular dilation. Previously, researchers theorized that vascular dilation was triggered by an agent named "endothelium-derived relaxing factor" or EDRF. With the association established by Furchgott, Murad and Ignarro, researchers now believe that NO is the dominant, if not exclusive EDRF and is directly related to the health and condition of the endothelium and the ability of the endothelium to dilate the arteries of a person. The Nature of Endothelium-Derived Relaxation Factor, R. Furchgott, Nov. 16, 1998, at the "www" website hscbklyn.edu/pharmacology/furch.htm; Research Interests: nitric oxide; cyclic gmp, cell signaling, second messengers, regulatory biology, molecular pharmacology, F. Murad, Nov. 15, 1998, at the "http" website girch z.med.uth.tmc.edu/faculty/fmurad/index.cfm; and, Nitric Oxide and Cyclic GMP Signal Transduction Mechanisms, L. Ignarro, Nov. 15, 1998, at the "www" website nuc.ucla.edu/html-docs/faculty-docs/ignarro.html. Accordingly, current research now indicates that NO is generated by the endothelium and is transmitted through the endothelium and that NO is a biomarker for vascular dilation.
Medical professionals have, in the past, sought to determine the health of a patient's vascular system by monitoring the physiological conditions or characteristics of the arteries in a patient's limb after reactive hyperemia. Reactive hyperemia occurs in a patient after a major artery has been blocked off or closed by a blood pressure cuff inflated slightly above systolic pressure for approximately five minutes. The limb, downstream from the blocked artery, suffers anoxia or severe hypoxia. Upon a sudden release of the blood pressure cuff, the endothelial cells lining the interior of the arterial wall react by generating NO and by dilating. This vascular dilation and expansion results in the expansion of resistive arterial vessels and associated muscles significantly downstream from site of the previously collapsed artery. The resistive arterial vessels enlarge based upon the NO biomarker, transmit NO through other parts of the endothelium and may cause reactive hyperemia in the limb. Reactive hyperemia is a significantly greater flow of blood through an artery, vein or limb as compared with normal blood flow therethrough. Blood flow is a characteristic of the artery and is typically a quantitative measurement of blood volume with respect to time (e.g. ml per minute). Generally, the phenomenon of reactive hyperemia lasts up to 10 minutes before return to pre-test pulse volume values.
Some medical professionals utilize pulse volume recorders to measure the peak pressure (mmHg) in the arteries immediately after the release of the blood pressure cuff and ischemia. However, these researches measure only the peak pressure during the reactive hyperemia and typically do not continuously measure blood volume or blood flow or the pulsatile blood volume change through the arteries in the limb during the entire reactive hyperemia episode, i.e., until return to the pre-episode state. The methods of pulse volume measurements have not been standardized by a national consensus panel of investigators.
Other researchers studying the effect of reactive hyperemia on a vascular system utilize ultrasound imaging techniques to capture an image of the brachial artery (the artery which is blocked to achieve reactive hyperemia in the arm of the patient) and measure the changing diameter of the brachial artery. Technicians measure the diameter of the artery before the ischemia (prior to reactive hyperemia and closure of the vascular system) by capturing electronic ultrasonic images. Subsequently, technicians attempt to detect and measure the largest expansion of the diameter of the brachial artery after ischemia and during the reactive hyperemia episode. These medical professionals then compute (with simple geometric equations) the expansion of the artery and the volume change of the artery. However, the use of an ultrasound image to measure the expansion of the brachial artery during reactive hyperemia has many technical problems that may jeopardize the measurement's accuracy and precision.
Researchers have observed that the brachial artery diameter typically expands about 0.3 mm during reactive hyperemia. Reproducibility of Brachial Ultrasonography and Flow-Mediated Dilation (FMD) for Assessing Endothelial Function, by K. L. Hardie, et al., Australian New Zealand Journal of Medicine, 27, pp.649-652, 1997 (this study revealed arterial diameter of 3.78 mm at rest; 3.89 mm during reactive hyperemia). Other studies show diameters of 3.92 mm at rest increasing to 4.13 mm during reactive hyperemia. Noninvasive Assessment of Endothelium-Dependent Flow-Mediated Dilation of the Brachial Artery, by A. Uehata et al, Vascular Medicine 2, pp. 87-92, 1997. Studies have shown that the effect of nitroglycerin treatment during reactive hyperemia increases the expansion of the arterial diameter by about 11%. Flow-Induced Vasodilation of the Human Brachial Artery is Impaired in Patient [over] 40 years of Age with Coronary Artery Disease, by E. Lieberman, et al., American Journal of Cardiology, 78, pp. 1210-1214, 1996. Nitroglycerin is converted into NO and this additional NO stimulates vascular dilation. This study has indicated that young people, without any indication of coronary artery disease (healthy individuals), exhibit an increase in the diameter of the brachial arterial on the order of 6.2%. In contrast, young people with coronary artery disease exhibit an arterial diameter increase of only 1.3%. This same study measured arterial diameters utilizing ultrasonic techniques and revealed measurement errors of plus or minus 1.1% for the diseased population typical (arterial expansion of 1.3%). Errors of 0.7% were noted during the ultrasonic measurement of the brachial arteries in the healthy population (typical arterial change of 6.2%). Accordingly, these studies show a coefficient of error or variation of almost 30% with utilization of ultrasonic techniques. These errors are caused by the acquisition of the electronic image data capturing the expansion of the brachial artery during reactive hyperemia, the measurement of the electronic image and the introduction of arithmetic errors into the calculation of the arterial diameter.
Currently, many researchers utilize ultrasonic techniques to noninvasively detect the increase of the diameter of the artery during reactive hyperemia. The use of ultrasonic imaging techniques has many problems. For example, the ultrasound technician operator must carefully place the ultrasound scanning head on and above the brachial artery at a certain x-y and z position relative to the patient's skin. The ultrasound head is typically placed a few inches above the crease in the patient's elbow. If the operator places the ultrasound head at a different location on another patient or if the operator places the ultrasound head at a different location on the same patient at a different clinical testing time, the data obtained during these inter-patient and intra-patient tests is not consistent. Further, the ultrasound operator must place the ultrasound head on the patient, move the ultrasound head longitudinally up and down the patient's arm, move the head laterally side to side about the arm and rotate the angle of the ultrasound head relative to the surface of the skin in order to obtain a clear electronic image of the brachial artery. This involves multiple eye-hand coordination by the operator since the operator views the image while he or she moves the ultrasound head over the patient's arm. Further, after the operator correctly positions and obtains a clear electronic image, the operator must then issue (a) a cuff release command to begin the reactive hyperemia and (b) a record command to the ultrasound equipment which begins recording the image. The ultrasound operator may also be required to move electronic calipers on the captured electronic image at the same time as he or she is capturing additional images in order to measure the expanded diameter of the brachial artery during reactive hyperemia. Specifically, the ultrasound operator quickly releases the blood pressure cuff which occluded the brachial artery for about five (5) minutes and initiates reactive hyperemia in the limb. During the first minute after cuff release, the ultrasound operator carefully positions the ultrasound head on the skin of the patient. During the next thirty seconds, the operator captures the ultrasound image of the expanded diameter of the brachial artery as a recorded electronic image and measures the increase of the arterial diameter. This measurement normally includes the use of electronic calipers on the display screen. In the third sixty second period, the operator continues to electronically monitor and store the image of the brachial artery as the arterial diameter reduces in size during the latter portions of the reactive hyperemia episode.
After the ultrasound operator captures this electronic image, the operator or other health professional can view or re-play the stored electronic image and seek to identify the largest expansion of the diameter of the brachial artery. Accordingly, it is difficult to obtain this data with ultrasound equipment, to replicate the test on the same patient, to replicate the same test on a different patient, to interpret the electronic image and to quantify the amount of arterial expansion.
These problems with respect to ultrasound imagery and the interpretation of the captured image have inhibited researchers from reproducing earlier experiments and confirming experiments conducted by other researchers and combining or correlating data from various studies. The current lack of standardization of methods prevents definitive studies among investigators.
Further, since ultrasonic imagery measures only an increase in the diameter of an artery, any error introduced by this measurement is amplified since it is squared in the mathematic formulas for the area A of a circle and the volume V of a tubular structure such as an artery. The equation for area A follows: EQU A=(1/4).pi.d.sup.2 Eq. 1
The equation for the volume V of a cylinder follows. EQU V=(1/4).pi.d.sup.2 1 Eq. 2
The length of the ultrasound head is utilized to estimate the length 1 of the generally cylindrical arterial vessel. This formula establishes the volume of the arterial segment and the change in volume of the arterial segment during reactive hyperemia. Accordingly, any error introduced into the measurement of the diameter d of the artery is squared by the volumetric formula Eq. 2 and the system operator can only estimate the length 1 of arterial segment based upon the size of the ultrasound head. This estimate of length 1 also introduces another element of error into the measurement of the volumetric change of the blood vessel during reactive hyperemia.
U.S. Pat. No. 5,718,232 to Raines, et al. and U.S. Pat. No. 5,630,424 to Raines, et al. describe a calibration system for measuring segmental blood volume changes in arteries and veins for pulse volume recorders. The pulse volume recorders described in Raines '232 and Raines '424 add or subtract a predetermined volume (approximately 1 ml) to or from the volume of the pneumatic blood pressure cuff system at each cuff pressure over a plurality or multiple levels of induced cuff pressure. Basically, Raines '232 and Raines '424 seek a solution to the problem that the pneumatic response of the blood pressure cuff system due to blood pressure pulse waves changes at each discrete level of induced cuff pressure (the response delta P changes at each cuff lever Pcuff 40, 50, 60, 70, 80, and 90 mmHg.). In order to measure and calibrate the blood pressure system at each discrete cuff level, the predetermined volumetric amount is added or withdrawn from the pneumatic system at that induced cuff pressure level. By measuring the pressure change at the time of the volumetric calibration pulse, the resulting pressure wave signal is a calibration pressure pulse. The sensed pressure wave signal at the induced cuff pressure is converted into a corrected blood volume signal using the ratio of the volumetric calibration pulse versus the calibration pressure pulse. This is a direct measurement of blood volume and a basis for blood flow at the induced pressure level.
Specifically, the Raines '232 and the Raines '424 patents utilize a blood pressure cuff placed around the limb of a patient. The blood pressure cuff was pumped up or inflated to certain predetermined cuff levels such as 40, 50, 60, 70 mmHg through 120 mmHg. At each discrete cuff pressure level Pcuff, the system was calibrated in order to obtain a corrected blood volume signal change at each cuff pressure level. After the corrected blood volume data was obtained, a ratio was generated between blood volume change in relation to the pressure change at the selected induced cuff pressure in order to determine the maximum value of the blood volume versus the sensed pressure differential. The maximal ratio of blood volume change versus blood pressure change at a particular cuff pressure provides an indication of the onset and the degree of atherosclerosis in humans as well as provides an indication of the health or condition of the vascular system and particularly of the peripheral vascular system. The contents and substance of U.S. Pat. No. 5,718,232 to Raines et al. and U.S. Pat. No. 5,630,424 to Raines et al. is incorporated herein by reference thereto. The relationship between atherosclerosis and the maximal ratio of delta V over delta P (peak arterial compliance) is disclosed in U.S. Pat. No. 5,241,963 to Shankar. The content of U.S. Pat. No. 5,241,963 is incorporated herein by reference thereto.